Professor Rod Devenish

Research Focus

Autophagy - eating your way out of trouble!

IntroductionAll eukaryotic cells degrade (or turnover) parts of their internal structure including organelles by a process called autophagy("self eating") that occurs in a specialized compartment of cells - the vacuole (in yeast) or the lysosome (in mammals). In yeast, autophagy is mainly involved in cellular homeostasis (removal of damaged organelles) and adaptation to starvation, but in multicellular organisms (mammals) it is involved in a variety of additional processes such as programmed cell death and development of different tissue-specific functions. Alterations in the levels of autophagy are linked to a growing number of pathological conditions including neurodegenerative diseases such Parkinson's, myopathies such as cardiomyopathic Danon's disease, some forms of cancer, and infection by pathogenic bacteria or viruses.

Current workThe turnover of mitochondria, the nucleus and other organelles by autophagy presumably serves as a means of quality control for organelle function. Mechanistically distinct forms of autophagy have been identified (see Figure 1). The molecular details and regulation of these processes and how they relate to organelle turnover are now becoming better understood, but we are a long way from having complete understanding. We are using fluorescent protein technology [Devenish et al.,2008; Mijaljia et al., 2011) together with other biochemical and molecular techniques, in yeast and mammalian cells to monitor turnover. This approach is providing new insights into the complex pathways and molecular mechanisms by which organelle autophagy occurs. We have established a ‘discovery pipeline' to systematically screen a number of different yeast gene libraries and identify the molecular components and networks required for the regulation of mitophagy. For example, using our "Rosella" fluorescent biosensor in yeast (Figure 2) we have uncovered OTP1, a gene involved in an early phase autophagy of mitochondria (mitophagy). Use of yeast as an experimental model first sparked the ‘explosion' of knowledge concerning mammalian autophagic processes and continues to contribute new findings and understanding to the field.

Autophagy as a host-cell response to bacterial infection.Successful microbial pathogens have evolved strategies to avoid or subvert autophagy thereby ensuring their survival within cells. Together with colleagues in the ARC Centre of Excellence in Structural and Functional Microbial Genomics (Ben Adler and John Boyce) we are looking at the molecular mechanisms by which the soil bacterium, Burkholderia pseudomallei achieves the avoidance or subversion of autophagy. In humans infection leads to Melioidosis, a disease endemic in tropical and subtropical areas. It is also a significant pathogen in many animals. This intracellular pathogen can escape from phagosomes into the host cytoplasm, where it replicates and infects adjacent cells. We are investigating the role played by autophagic processes in the intracellular life-cycle of B. pseudomallei in phagocytic cell lines, using confocal microscopy, intracellular survival assays and in vivo infection models. Our results (Gong et al., 2011) show that an autophagy-related pathway, LC3-associated phagocytosis (LAP) provides a defence system for macrophage cells against invading B. pseudomallei. However LAP is relatively ineffective and most bacteria escape to the cytosol where they efficiently evade capture by canonical autophagy. Presumably various bacterial proteins act as effectors that interact with host cell trafficking factor(s) and contribute to modulation of host cell biology. We are seeking to identify such proteins and their functions during infection.

Project Areas for Prospective Students1. Autophagy of organelles, focusing on mitochondrial and nucleus turnover.2. Autophagy in infectious disease; how autophagy can be avoided or subverted in microbial infection of mammalian cells.3. Developing new biosensors for accelerating autophagy research.